Spectrometric analysis of large, labile, polar molecules is of great importance to research in a broad spectrum of scientific disciplines. This proposal is concerned with the relatively low sensitivity of secondary ionization mass spectrometry performed on liquid sample matrices, a form of mass spectrometry capable of analyzing large, organic molecules. An opportunity exists for increasing the sensitivity of this important technology by as much as two or three orders of magnitude; more specifically, through a combination of systematic investigation and innovative use of a liquid metal ion source in conjunction with a fine focused ion column, it should be possible to greatly reduce the absolute amount of analyte required for analysis, to increase the efficiency of ionizing the analyte molecules, and to substantially increase the efficiency of collecting the analyte ions for transmission through the mass analyzer. A successful outcome from the program outlined in this proposal would have a significant technological impact on biomedical research and would stimulate further advances in high sensitivity analyses by mass spectrometry. Moreover, the development of a liquid metal in focusing column for ultra-sensitive, liquid matrix secondary ionization mass spectrometry could help the Nation regain some of its technical and economic competitiveness in the important field of mass spectrometry.